The hospital frailty risk score effectively predicts adverse outcomes in patients with atrial fibrillation in the intensive care unit

Background Atrial fibrillation (AF) and frailty are significant global public health problems associated with advancing age. However, the relationship between frailty and older patients with AF in the intensive care unit (ICU) has not been thoroughly investigated. This study aimed to investigate whether the hospital frailty risk score (HFRS) is associated with adverse outcomes in older patients with AF in the ICU. Methods This was the first retrospective analysis of older patients with AF admitted to the ICU between 2008 and 2019 at a tertiary academic medical center in Boston. The HFRS was used to measure frailty severity. The outcomes of interest were in-hospital and 30-day mortality and the incidence of sepsis and ischemic stroke. Results There were 7,792 participants aged approximately 80 years, almost half (44.9%) of whom were female. Among this group, 2,876 individuals were identified as non-frail, while 4,916 were classified as frail. The analysis revealed a significantly greater incidence of in-hospital (18.8% compared to 7.6%) and 30-day mortality (24.5% versus 12.3%) in the frail group. After accounting for potential confounding factors, a multivariate Cox proportional hazards regression analysis revealed that frail participants had a 1.56-fold greater risk of mortality within 30 days (95% CI = 1.38–1.76, p < 0.001). Conclusions Frailty is an independent risk factor for adverse outcomes in older patients with AF admitted to the ICU. Therefore, prioritizing frailty assessment and implementing specific intervention strategies to improve prognostic outcomes are recommended.


Introduction
Atrial brillation (AF), the most prevalent cardiac arrhythmia, exhibits an age-correlated increase in incidence and a steadily increasing incidence 1,2 .It is a precursor to severe complications, including stroke and heart failure 3 , and is intricately linked to various other adverse health consequences 4,5,6 .
Notably, approximately one-sixth of patients in the intensive care unit (ICU) present with AF 7 , a condition that signi cantly correlates with an inferior clinical prognosis 8,9 .Consequently, AF is a signi cant public health issue, placing a considerable burden on societal resources and healthcare infrastructures 10,11 .
Frailty is a clinical syndrome characterized by reduced physiological capacity, which increases individuals' susceptibility to stressors 12 .With the rapidly expanding aging population, the prevalence of frailty is projected to rise 13 , and frailty is becoming a signi cant public health concern.Among patients with AF, frailty is prevalent 14 , which increases their risk of negative health events 15 .Frailty presents a challenge in managing older AF patients in the ICU, requiring tailored care strategies.Despite its importance, there is a lack of research on frailty in this demographic population, highlighting a gap in clinical guidance.Therefore, this study aimed to determine the relationship between frailty and adverse health outcomes in older ICU patients with AF.This study is the rst to predict adverse outcomes in older patients with AF in the ICU by using the Hospital Frailty Risk Score (HFRS).Based on previous research and clinical expertise 9,16,17 , we propose that frailty can independently predict adverse outcomes, including mortality, sepsis and ischemic stroke, in older patients with AF in the ICU.The probability of adverse events increases with increasing HFRS score.

Data source
This retrospective observational study used data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database 18,19 .The database provides extensive clinical information on tens of thousands of patients treated at Beth Israel Deaconess Medical Center in Boston, Massachusetts between 2008 and 2019.This study aimed to analyse the data and draw conclusions based on the ndings.The MIMIC-IV combines electronic medical records from different sources, providing researchers with a vast amount of data that includes patient demographics, vital statistics, laboratory results, and diagnoses.The diagnoses were made using the International Classi cation of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) codes 20,21 .As the data in this database were deidenti ed, informed consent from patients was not required for this study.To ensure appropriate access and use of this database, our team has ensured that one of the authors has completed the required training and secured certi cation to access the database (Record ID: 57086222).

Study population
This study examined the rst admission of older patients with AF to the ICU.Diagnoses were determined using the ICD-9 code 42731 and the ICD-10 codes I48, I480, I481, I4811, I4819, I482, I4820, I4821, I489, and I4891 22 .HFRS was used to evaluate these patients, categorizing them into frail (HFRS ≥ 5) and nonfrail (HFRS < 5) groups 23,24 .Patients who had an ICU stay of less than 24 hours and who were under the age of 65 were excluded.The study included 7,792 individuals.Figure 1 shows the detailed screening process.

Data Extraction
The study used structured query language (SQL) to extract the data 20 .The following data were extracted: (1) general patient information; (2) treatments and medications; (3) scores; (4) vital signs; (5) laboratory tests; (6) comorbidities; and (7) adverse outcomes.Notably, vital signs, laboratory test results, and illness severity score data were extracted from the rst measurement on the day of ICU admission.
Sepsis was diagnosed according to the Sepsis-3 criteria 25 .Comorbidities were identi ed using ICD-9 and ICD-10 codes.The percentage of missing data for all variables did not exceed 10%.For variables with missing data rates less than 10%, we used the 'mice' package and random forest method for multiple imputation to more accurately estimate and impute the missing data 26 .

Exposure (frailty assessment)
This study utilized HFRS as the primary exposure factor 27 .The HFRS is a newly established and validated frailty assessment tool that uses routinely gathered data.It comprises 109 ICD codes that ag patients at elevated risk for adverse outcomes, making implementation straightforward.Supplementary Table 1 provides a detailed list of the items and their structure.Gilbert et al. formulated HFRS using ICD-10 codes 28 .This investigation extended the application of HFRS to include both ICD-9 and ICD-10 codes for extracting diagnostic data from the MIMIC-IV database.The 109 HFRS subitems were converted from ICD-10 to ICD-9 codes using general equivalence mapping from the Centers for Medicare and Medicaid Services (https://www.cms.gov) 29.The evaluation of HFRS items is underpinned by the compilation of these mappings.To simplify the classi cation of frailty status in the statistical analysis and enhance the interpretability of the results, patients with HFRS scores less than 5 were de ned as 'non-frail', while those with HFRS scores of 5 or more were de ned as 'frail' 24,23 .

Study outcomes
This study primarily focused on in-hospital and 30-day mortality rates while also examining secondary outcomes such as sepsis and ischemic stroke.The date of patient death was obtained from the 'dod' column in the 'patients' table, and survival time was calculated from the time of admission to the ICU minus the time of death.The MIMIC-IV database ensured a minimum follow-up time of one year for each patient record 30 .Sepsis was diagnosed based on the Sepsis-3 criteria 25 .Ischaemic stroke patients were diagnosed using the ICD-9 codes 433, 434, 436, 437.0, and 437.1 and the ICD-10 codes I63, I65, and I66 31 .

Covariates
Covariates, which are elements potentially linked to the study's outcomes but not the primary focus of analysis, were carefully chosen through a review of the literature, domain expertise, and data accessibility 1,32,33 .The analysis was adjusted for several variables, including age, sex, race, disease severity score (SOFA score), Charlson Comorbidity Index (CCI) score, Glasgow Coma Scale (GCS) score), falls, weight, comorbidities (dementia, ischaemic stroke, diabetes, congestive heart failure, hypertension), and medications and laboratory indicators (warfarin and international normalized ratio).
Covariates were adjusted based on the characteristics of adverse health outcomes in this study.

Statistical analysis
Following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines 34 , this study began with a descriptive statistical analysis to identify differences between frail and non-frail groups.The median values and interquartile ranges are presented for continuous variables that deviated from a normal distribution, and intergroup comparisons were performed using the Wilcoxon rank-sum test.Frequencies and percentages were used to depict categorical variables, and the chi-square test was used to identify differences between groups.Kaplan-Meier survival curves were generated in subsequent phases to illustrate 30-day survival rates across both cohorts, and the log-rank test was used to evaluate disparities in survival distributions.Cox proportional hazards regression models were used to investigate the correlation between HFRS scores and mortality rates.Logistic regression models were used to assess the associations between HFRS scores and in-hospital mortality, sepsis, and ischemic stroke.Hazard ratios (HRs) and odds ratios (ORs) were calculated along with their 95% con dence intervals (CIs).To ensure the accuracy of our results, we conducted a Schoenfeld residual test to verify the model's adherence to the proportional hazards assumption before performing multivariable Cox regression.Similarly, prior to multivariable logistic regression, we tested for multicollinearity among variables using variance in ation factor (VIF).Visual analysis of the associations between HFRS and in-hospital and 30-day mortality was performed using restricted cubic splines.Subgroup analyses were conducted to examine the potential impact of variables such as age, sex, race, congestive heart failure, hypertension, ischemic stroke, and warfarin use on the outcomes.
The statistical analysis was performed using R software (version 4.3.2,https://www.r-project.org/).P < 0.05 was considered to indicate statistical signi cance in this study.

Sensitivity analysis
The study's sensitivity analysis focused on two main aspects.First, propensity score matching (PSM) was used to ensure the robustness and stability of the results 35 , effectively reducing confounding bias.A multivariable logistic regression model was constructed for this study using the following covariates: age, sex, race, disease severity score (SOFA, GCS, CCI), falls, weight, dementia, ischemic stroke, diabetes, congestive heart failure, hypertension, warfarin, and international normalized ratio.The 1:1 full matching algorithm was used for matching.After a successful match, we compared the baseline differences between the groups and calculated the standardized mean difference (SMD) for all covariates to validate balance.An SMD value below 0.1 typically indicates good balance between the groups.Second, we assessed the E-value.This is a measure used to assess the potential effect of unmeasured confounders on the results of observational studies 36 .A web-based online calculator (https://www.evaluecalculator.com/evalue/) was used to calculate the E-value.This metric helps to determine whether observed associations may be in uenced by unmeasured potential factors.In general, a higher E value indicates more robust results, as confounders are harder to explain or overturn.

Baseline characteristics of participants
The baseline demographics of the 7,792 older patients with AF studied in this study are shown in Table 1.The median HFRS score was approximately 7 (interquartile range [IQR]: 3.2-11.1).Patients were divided into two cohorts according to frailty status: non-frail (n = 2,876) and frail (n = 4,916).The majority of patients were Caucasian (77.0%), the median age was approximately 80 years, and 3,495 were female (44.9%).Compared with their non-frail counterparts, the frail cohort experienced longer hospital and ICU stays, presented with greater disease severity, exhibited a greater number of comorbidities, and were more likely to undergo various treatments.Furthermore, the frail group was found to have an increased risk of adverse events (all p < 0.05).

Primary outcomes
The study population had an overall in-hospital mortality rate of 14.7% and a 30-day all-cause mortality rate of 20.0%.The frail group had signi cantly greater in-hospital mortality (18.8% vs. 7.6%, p < 0.001) and 30-day mortality (24.5% vs. 12.3%, p < 0.001) compared to the non-frail group.The Kaplan-Meier survival curves (Fig. 2) indicate a signi cantly lower survival probability for frail patients compared to non-frail patients over a 30-day follow-up period (log-rank test; p < 0.001).Cox proportional hazards regression analysis demonstrated that frail patients face a markedly increased risk of 30-day mortality relative to non-frail patients (Table 2), even after adjusting for confounding variables (adjusted HR: 1.56, 95% CI: 1.38-1.76;E-value: 2.49, p < 0.001).Additionally, logistic regression analysis revealed a signi cantly greater in-hospital mortality rate in the frail group than in the non-frail group (adjusted OR: 2.08, 95% CI: 1.76-2.47;E-value: 3.58, p < 0.001).The nonlinear relationship between the OR/HR for inhospital and 30-day mortality and HFRS was demonstrated through the use of restricted cubic spline curves.An increasing trend in OR/HR was observed as the incidence of HFRS increased (Supplementary Fig. 1).

Subgroup Analysis
To examine the association between frailty and 30-day mortality in different subgroups, subgroup analyses were performed.All seven subgroups analysed (Fig. 3) showed statistically signi cant differences.

Sensitivity analysis
After PSM in the original cohort population, we achieved group balance and improved comparability between covariates.The differences in baseline characteristics between the two groups in the matched cohort were re-evaluated (Supplementary Table 2).The corresponding changes in the SMD are shown in Supplementary Fig. 2. Consistent results were found in the matched cohort, which aligns with those observed in the original cohort population (Supplementary Table 3).These ndings indicate that frailty is associated with adverse health outcomes in older patients with AF.

Discussion
This study presents a comprehensive analysis of AF patients in the ICU using the large-scale publicly available MIMIC-IV dataset.The results indicate that frailty level, represented by HFRS, remains an independent predictor of increased in-hospital and 30-day mortality risks in this population, even after accounting for other potential confounding factors.Additionally, frail patients were found to have a higher risk of sepsis and ischemic stroke compared to those in the non-frail group.These ndings highlight the usefulness of HFRS as a tool for screening for frailty among ICU AF patients.They also demonstrated the negative impact of frailty in this patient group and provided valuable insights for developing targeted management and care approaches in the ICU.
Frailty is a major focus of international public health research with signi cant implications for disease management and population health 37 and is more prevalent in older age groups 38 .Although it is well known that multiple factors, such as age, sex and comorbidities, are associated with adverse outcomes in patients with AF 39,40,41 , our study highlights the prospective utility of HFRS in this context 27,42 .
Although the impact of frailty on health outcomes in AF patients has been previously studied 43,44 , there remains a gap in research investigating the relationship between frailty, as assessed by the HFRS, and patients with AF.Our analysis retrospectively examined 7,792 critically ill older patients with AF to address this research gap.The signi cance of frailty, as determined by HFRS, may be attributed to various factors.First, frailty is often associated with systemic in ammatory responses, neuroendocrine imbalances, and cardiovascular dysfunction 13 .These conditions may exacerbate cardiac challenges for patients with AF, leading to worse clinical outcomes.Second, the HFRS can serve as a multidimensional assessment tool for older, critically ill patients.Patients classi ed as frail in the ICU often experience various complications, such as neurodegenerative disorders, cerebrovascular diseases, renal insu ciency, and malnutrition, all of which contribute to a negative prognosis 4,45,46,47 .Furthermore, patients with AF may require increased medical attention and resources, such as extended periods of mechanical ventilation and renal replacement therapy 48 .This elevates treatment complexity and associated risks, potentially worsening their overall prognosis.Therefore, HFRS is a valuable tool for predicting adverse outcomes in these patients.Prompt recognition and intervention for individuals at risk of frailty is crucial, particularly within the high-stakes setting of the ICU, to provide specialized care and management to this vulnerable group.
Sepsis is a common complication in ICU, which can lead to high mortality rates and put signi cant pressure on ICU resources 49,50 .Patients with AF may have compromised cardiac function 51 , making the heart more vulnerable to infections or bacteremia, which increases the risk of sepsis.Previous studies have focused on AF caused by sepsis 52,53 , and our study con rms the usefulness of HFRS in predicting sepsis risk in patients with AF.This may be due to the unique composition of HFRS items, which not only re ect the degree of frailty but also predict the risk of complications during hospitalization 27 .In addition, frailty-induced physiological decline also increases the susceptibility of patients to infections, such as sepsis 54 .The HFRS offers clinicians a straightforward screening tool to identify sepsis risk in patients with AF.
Patients with ischaemic stroke who are admitted to the ICU face an increased short-term risk of mortality 55 .Therefore, early detection and treatment are crucial for reducing mortality rates 45 .Previous research by Renedo et al. has established a link between frailty, as measured by the HFRS, and an elevated risk of ischemic stroke 56 .Similarly, our research supports the clinical e cacy of HFRS in predicting the risk of ischemic stroke in patients with AF.HFRS is straightforward and accessible, eliminating the need for additional laboratory tests.This provides clinicians with a viable method to quickly and accurately evaluate the risk of adverse outcomes in critically ill patients with AF.
This study has limitations, some of which are inherent to retrospective research.Although we adjusted for factors such as disease severity scores and comorbidities, the stage and severity of AF can impact patient prognosis.However, because this study was retrospective, we were unable to evaluate any additional pertinent information.Second, this study was conducted solely at a tertiary academic center and focused on critically ill older patients with AF.Therefore, the generalizability of the study results may be limited, particularly regarding their applicability to older populations in home or nursing home settings, which requires further investigation.Third, there is a slight inherent inaccuracy in the HFRS score due to variability in recording practices among different healthcare institutions.This is particularly relevant considering the presence of both ICD-9 and ICD-10 codes in the MIMIC-IV database and our utilization of their conversion to construct the HFRS.We were unable to validate the validity of the HFRS score or ensure interobserver consistency, which could affect its clinical applicability, given the retrospective nature of this study.Future research should focus on prospective multicentre designs to enhance the generalizability of the results.Furthermore, it is recommended that more comprehensive and standardized assessment tools be incorporated to gain a better understanding of the correlation between AF and other potential covariates.

Conclusion
In conclusion, our ndings emphasize the importance of using HFRS for frailty assessment to predict inhospital mortality, 30-day mortality, sepsis, and ischemic stroke risk among critically ill older patients with AF.This score plays a crucial role in managing this vulnerable population and provides valuable insights for future clinical practice and research.

Informed consent
Data extracted from the MIMIC-IV database do not require individual informed consent because the research data are publicly available, and all patient data are deidenti ed.

Note:
▲ In our study, frailty status was de ned based on the total score of the Hospital Frailty Risk Score (HFRS): the non-frail group was de ned as those with an HFRS scores of less than 5, frail group was de ned as those with an HFRS score of 5 or higher.

Note:
(HFRS): the non-frail group was de ned as those with an HFRS scores of less than 5, frail group was de ned as those with an HFRS score of 5 or higher.#Cox proportional hazards regression models were used to calculate hazard ratios (HR) with 95% con dence intervals (CI).
•Logistic regression models were used to calculate odds ratios (OR) with 95% con dence intervals (CI).*Signi cant difference between patients with dementia between two groups (p < 0.05).
In-hospital mortality and 30-day mortality were adjusted for age, sex, race, Charlson Comorbidity Index (CCI), Glasgow Coma Scale (GCS), dementia, ischemic stroke, diabetes, congestive heart failure, hypertension, fall, weight, warfarin and international normalized ratio; Sepsis and ischemic stroke were adjusted for age, sex, race, Sequential Organ Failure Assessment (SOFA) and CCI.

Declarations
Ethics approval and Consent to participate The Medical Information Mart for Intensive Care IV (MIMIC-IV) database was supported by grants from the National Institute of Biomedical Imaging and Bioengineering (NIBIB) of the National Institutes of Health (NIH) under award numbers R01-EB001659 (2003-2013) and R01-EB017205 (2014-2018) and approved by the Institutional Review Boards of Beth Israel Deaconess Medical Center (Boston, MA) and the Massachusetts Institute of Technology (Cambridge, MA).

Figures
Figures

Table 2
Logistic regression: Association between frailty and primary/secondary outcomes.